Many human retinal diseases cause vision loss by partial to complete destruction of the vascular layers of the eye that include the choroid and choriocapillaris, both of which nourish the outer anatomical retina and a portion of the inner anatomical retina of the eye.
Many other retinal diseases cause vision loss due to partial to complete degeneration of one or both of the two anatomical retinal layers directly, due to inherent abnormalities of these layers. The components of the retinal layers include Bruch's membrane and retinal pigment epithelium which comprise the “outer anatomical retinal layer”, and the photoreceptor, outer nuclear, outer plexiform, inner nuclear, inner plexiform, amacrine cell, ganglion cell and nerve fiber layers which comprise the “inner anatomical retinal layer”, also known as the “neuroretina”. The outer portion of the neuroretina is comprised of the photoreceptor and bipolar cell layers and is also known as the “outer retina” which is to be distinguished from the “outer anatomical retinal layer” as defined above. Loss of function of the outer retina is commonly the result of dysfunction of the outer anatomical retinal layer that provides nourishment to the outer retina and/or to direct defects of the outer retina itself. The final common result, however, is dysfunction of the outer retina that contains the light sensing cells, the photoreceptors. Some of these “outer retina” diseases include age-related macula degeneration, retinitis pigmentosa, choroidal disease, long-term retinal detachment, diabetic retinopathies, Stargardt's disease, choroideremia, Best's disease, and rupture of the choroid. The inner portion of the neuroretina, however, often remains functionally and anatomically quite intact and may be activated by the appropriate stimuli.
While researchers have reported efforts to restore visual function in humans by transplanting a variety of retinal cells and retinal layers from donors to the subretinal space of recipients, no sustained visual improvement in such recipients has been widely accepted by the medical community.
Multiple methods and devices to produce prosthetic artificial vision based on patterned electrical stimulation of the neuroretina in contact with, or in close proximity to, the source of electrical stimulation are known. These devices typically employ arrays of stimulating electrodes powered by photodiodes or microphotodiodes disposed on the epiretinal side (the surface of the retina facing the vitreous cavity) or the subretinal side (the underneath side) of the neuroretina. Such methods and implantable prosthetic electrical devices, designed to replace missing and damaged cells, are used to partially treat blindness in which the outer retinal cells have degenerated, but where the inner retinal layer is at least partially intact. Known devices typically employ arrays of stimulating electrodes powered by photodiodes or microphotodiodes (components that produce an electrical current or voltage potential in response to light) disposed on the epiretinal side or the subretinal side of the neuroretina. These devices can improve light perception. For example, subretinal implantation at discrete retinal locations has been shown to mimic light perception-mediated signaling; in one study (Chow and Chow, 1997), electrodes powered by external photodiodes were implanted in the subretinal space of adult rabbits. When the photodiodes, but not the rabbits' eyes themselves, were exposed to a flash of light, signaling in the brain visual cortex resembled that induced by light stimulation of the eyes. Further animal studies have demonstrated the safety and efficacy of such devices (Peachey and Chow, 1999).
Examples of devices designed to be implanted predominantly subretinally include “Surface Electrode Microphotodiodes” (SEMCPs) (Chow, U.S. Pat. No. 5,024,223, 1991), Independent Surface Electrode Microphotodiodes (ISEMCPs and ISEMCP-Cs) (Chow and Chow, U.S. Pat. No. 5,397,350, 1995; Chow and Chow, U.S. Pat. No. 5,556,423, 1996), multi-phasic microphotodiode retinal implants (MMRIs, such as MMRI-4) (Chow and Chow, U.S. Pat. No. 5,895,415, 1999), and VGMMRIs (Chow and Chow, U.S. application Ser. No.09/539,399, 2000). All these devices can be generically called Silicon Retinal Prostheses (SRP). MMRIs and VGMMRIs are designed to be used by themselves alone, or with an externally worn adaptive imaging retinal stimulation system (AIRES). These implants effectively improve perception of light and dark.
Cellular electrical signals also play important developmental roles, enabling nerve cells to develop and function properly. For example, nerve cells undergo constant remodeling, or “arborization”, during development related to electric signaling. First an extensive preliminary network is formed that is then “pruned” and refined by mechanisms that include cell death, selective growth, loss of neurites (axonal and dendritic outgrowths), and the stabilization and elimination of synapses (Neely and Nicholls, 1995). If a neuron fails to exhibit or is inhibited from transducing normal electrical activity during arborization, axons fail to retract branches that had grown to inappropriate positions.
The application of electric currents to organ systems other than the eye is known to promote and maintain certain cellular functions, including bone growth, spinal cord growth and cochlear spiral ganglion cell preservation (Acheson et al., 1991; Dooley et al., 1978; Evans et al., 2001; Kane, 1988; Koyama et al., 1997; Lagey et al., 1986; Leake et al., 1991; Leake et al., 1999; Politis and Zanakis, 1988a; Politis and Zanakis, 1988b; Politis and Zanakis, 1989; Politis et al., 1988a; Politis et al., 1988b).
In other studies, the application of growth and neurotrophic-type factors was found to promote and maintain certain retinal cellular functions. For example, brain-derived neurotrophic factor (BDNF), neurotrophin−4 (NT−4), neurotrophin−5 (NT−5), fibroblastic growth factor (FGF) and glial cell line-derived neurotrophic factor (GDNF) have been shown to enhanced neurite outgrowth of retinal ganglion cells and to increase their survival in cell culture. GDNF has been shown to preserve rod photoreceptors in the rd/rd mouse, an animal model of retinal degeneration. Nerve growth factor (NGF) injected into the intra-ocular area of the C3H mouse, also a model of retinal degeneration, results in a significant increase of surviving photoreceptor cells compared to controls (Bosco and Linden, 1999; Caleo et al., 1999; Carmignoto et al., 1989; Cui et al., 1998; Frasson et al., 1999; Lambiase and Aloe, 1996; Reh et al., 1996). No methods or devices, however, to improve the general inherent visual function of damaged retinal cells distant from a source of electrical stimulation through the use of chronic electrical stimulation applied to the neuroretina from either within the eye or in direct contact with the outside of the eye are known. Also unknown is the application of growth or neurotrophic-type factors to further improve the ability of an electrical retina prosthesis that applies chronic electrical stimulation to the eye to improve retinal visual function.